Method for lowering sorbitol levels using spiro-imides

ABSTRACT

A series of spiro-imide compounds and their base salts with pharmacologically acceptable cations are disclosed. These particular compounds are useful in therapy as agents for the control of certain chronic diabetic complications. Preferred member compounds include 2,3-dihydro-spiro-[1H-indene-1,3&#39;-pyrrolidone]-2&#39;,5&#39;-dione, 2,3-dihydro-spiro-[1H-indene-2,3&#39;-pyrrolidine]-2&#39;,5&#39;-dione, 3,4-dihydro-spiro-[2H-naphthalene-1,3&#39;-pyrrolidine]-2&#39;,5&#39;-dione, 3,4-dihydro-spiro-[2H-naphthalene-1,3&#39;-piperidine]-2&#39;,6&#39;-dione, 6-chloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3&#39;-pyrrolidine]-2&#39;,5&#39;-dione and 6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3&#39;-pyrrolidine]-2&#39;,5&#39;-dione. Methods for preparing these compounds from known starting materials are provided.

BACKGROUND OF THE INVENTION

This invention relates to new and useful imide derivatives of principalinterest to those in the field of medicinal chemistry and/orchemotherapy. More particularly, it is concerned with a novel series ofspiro-imide compounds, which are of especial value in view of theirability to effectively control certain chronic complications arisingfrom diabetes mellitus (e.g., diabetic cataracts, retinopathy andneuropathy). The invention also includes a new method of therapy withinits scope.

In the past, various attempts have been made by numerous investigatorsin the field of organic medicinal chemistry to obtain new and betteroral antidiabetic agents. For the most part, these efforts have involvedthe testing of various organic compounds in an endeavor to determinetheir ability to lower blood sugar (i.e., glucose) levels. However, inthe search for newer and still more effective antidiabetic agents,little is known about the effect of other organic compounds inpreventing or arresting certain chronic complications of diabetes, suchas diabetic cataracts, neuropathy and retinopathy, etc. Nevertheless, K.Sestanj et al. in U.S. Pat. No. 3,821,383 do disclose that certainaldose reductase inhibitors like1,3-dioxo-1H-benz[d,e]isoquinoline-2(3H)-acetic acid and someclosely-related derivatives thereof are useful for these purposes eventhough they are not known to be hypoglycemic. These compounds functionby inhibiting the activity of the enzyme aldose reductase, which isprimarily responsible for catalyzing the reduction of aldoses (likeglucose and galactose) to the corresponding polyols (such as sorbitoland galactitol) in the human body. In this way, unwanted accumulationsof galactitol in the lens of galactosemic subjects and of sorbitol inthe lens, retina, peripheral nervous system and kidney of variousdiabetic subjects are thereby prevented or reduced. As a result, thesecompounds control certain chronic diabetic complications, includingthose of an ocular nature, since it is already known in the art that thepresence of polyols in the lens of the eye quite often leads to cataractformation and concomitant loss of lens clarity.

SUMMARY OF THE INVENTION

In accordance with the present invention, it has now been rathersurprisingly found that various spiroimide compounds are extremelyuseful when employed in therapy as agents for the control of certainchronic complications arising in a diabetic subject even though they arenot outstanding aldose reductase inhibitors per se. More specifically,the novel method of treatment of the present invention involves treatinga diabetic host to prevent or alleviate diabetes-associated chronicocular and neuritic complications by administering to said host aneffective amount of a compound of the formulae: ##STR1## and the basesalts thereof with pharmacologically acceptable cations, wherein W is--(CH₂)_(n) --; X is hydrogen, chlorine, lower alkyl or lower alkoxy; X¹is hydrogen, fluorine, chlorine, bromine, lower alkyl, lower alkoxy orphenyl, with the proviso that when X¹ is fluorine, bromine or phenyl, Xis hydrogen; Y is oxygen or sulfur; Z is W, Y or Q wherein Q isoxosulfur or dioxosulfur; m is one or two; and n is zero or one. Thesecompounds possess the ability to markedly reduce or even inhibitsorbitol accumulation in the lens and peripheral nerves of variousdiabetic subjects.

The compounds of this invention which are novel are those of formula Iwherein Z is Z or Q as previously defined or Z is (CH₂)_(n) and n iszero. Additionally, those compounds of formula II per se are also allnovel compounds. Accordingly, the novel compounds of this inventioncomprise spiro-imides of the formulae: ##STR2## and the base saltsthereof with pharmacologically acceptable cations, wherein W is--(CH₂)_(n) --; X is hydrogen, chlorine, lower alkyl or lower alkoxy; X¹is hydrogen, fluorine, chlorine, bromine, lower alkyl, lower alkoxy orphenyl, with the proviso that when X¹ is fluorine, bromine or phenyl, Xis hydrogen; Y is oxygen or sulfur; V is oxygen, sulfur, oxosulfur ordioxosulfur; m is one or two; and n is zero or one.

Of especial interest in this connection are such typical and preferredmember compounds of the invention as2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione,2,3-dihydro-spiro-[1H-indene-2,3'-pyrrolidine]-2',5'-dione,3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione,3,4-dihydro-spiro-[2H-naphthalene-1,3'-piperidine]-2',6'-dione,6-chloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dioneand6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dione,respectively. These key compounds are all particularly effective inlowering sorbitol levels in the sciatic nerve and lens of diabeticsubjects as well as galactitol levels in the lens of galactosemicsubjects for the present purposes at hand. The preferred compounds are,as previously indicated, all new compounds with the sole exception of3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione which,although a known compound, was not previously recognized to be of valuefor the herein disclosed use.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the process employed for preparing the compounds ofthis invention of formula I when m is one and of formulae IA-II aspreviously defined, an appropriately substituted carbonyl ring compound,such as the corresponding 1-indanone, 2-indanone, 1-tetralone,4-chromanone, thiochroman-4-one, 6,7-dihydrobenzo(b)furan-4(5H)-one and6,7-dihydrobenzo(b)thiophene-4(5H)-one, of the respective formulae:##STR3## wherein W, X, X¹, Y and Z are all as previously defined, iscondensed with a lower alkyl α-cyanoacetate to give the correspondingcyano-iylidene acetate such as, for example,α-cyano-α-(2,3-dihydro-1H-indene-1-ylidene)acetic acid, which is thentreated with potassium cyanide to form the corresponding dicyanocompound followed by acid hydrolysis in a conventional manner to yieldthe corresponding dicarboxylic acid and finally, heat treatment of thelatter compound with ammonium hydroxide to ultimately yield the desiredspiro-imide final product of the structural formulae previouslyindicated. In practice, the last step of the process is usuallyconducted by heating the reaction mixture in an oil bath at hightemperatures and preferably at a temperature that is in the range offrom about 200° C. up to about 300° C., i.e., until at least all thevolatile material is removed from the mixture and the resultant productforms a homogeneous mass. In this way, 1-indanone is converted viaα-cyano-α-(2,3-dihydro-1H-indene-1-ylidene)acetic acid ethyl ester andα-cyano-α-(2,3-dihydro-1H-indene-1-yl)butanedioic acid, respectively, to2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione per se.

On the other hand, compounds of the invention of formula I where m istwo are best prepared by a series of reactions starting from thecorresponding α-cyano ring compound of the formula: ##STR4## wherein X,X¹ and Z are each as previously defined, which series of reactionsinvolves treating said starting material with 3-bromopropanenitrile inthe presence of a basic condensing agent like sodium hydride to form thecorresponding dinitrile, followed by alkaline hydrolysis of the lattercompound to yield the monoamide of the corresponding dicarboxylic acidand finally, heat treatment of the latter acid-amide with ammoniumhydroxide in the same manner as that described previously for the laststep of the first process to ultimately yield the desired spiro-imide ofstructural formula I wherein m is two. In this way, α-cyanotetralin isconverted viaα-(3,4-dihydro-2H-naphthalene-1-yl)-n-pentane-1,5-dinitrile andα-(3,4-dihydro-2H-naphthalene-1-yl)-n-pentane-1,5-dioic acid monoamide,respectively, to3,4-dihydro-spiro-[2H-naphthalene-1,3'-piperidine]-2',6'-dione per se.

Compounds of the invention in which Z of formula I is Q and Q is##STR5## can be prepared from those compounds wherein Z is sulfur bymerely oxidizing the latter group of compounds in accordance withstandard techniques well known to those skilled in the art. Forinstance, the use of sodium periodate in this connection leads to theformation of the oxosulfur compounds, while peroxy acids like peraceticacid, perbenzoic acid and m-chloroperoxybenzoic acid, etc., arepreferably employed to afford the corresponding dioxosulfur compounds.On the other hand, certain compounds of the invention having a ringsubstituent (X, X¹, etc.) which is halogen (as previously defined) mayalternatively be prepared from the corresponding unsubstituted compoundswherein at least one of X and X¹ is hydrogen by means of directhalogenation techniques well known to those in the field of syntheticorganic chemistry.

The ketone starting materials (i.e., carbonyl ring compounds) requiredfor preparing the spiro-imide intermediates of this invention are, forthe most part, known compounds and are either readily availablecommercially, like 1-indanone, 2-indanone, 6-chloro-4-chromanone and6,7-dihydrobenzo(b)thiophene-4(5H)-one, etc., or else they can easily besynthesized by those skilled in the art starting from common chemicalreagents and using conventional methods of organic synthesis. Forinstance, 6-fluoro-4-chromanone is obtained by condensingβ-(p-fluorophenoxy)propionic acid in the presence of polyphosphoricacid, while 6,7-dichlorothiochroman-4-one is obtained by condensingβ-(3,4-dichlorophenylthio)propionic acid in the presence of concentratedsulfuric acid. In both cases, the starting organic acid is ultimatelyderived from a commercially available compound.

The chemical bases which are used as reagents in this invention toprepare the aforementioned pharmaceutically acceptable base salts arethose which form non-toxic salts with the herein described acidicspiroimides such as2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione, for example.These particular non-toxic base salts are of such a nature that theircations are essentially non-toxic in character over the wide range ofdosage administered. Examples of such cations include those of sodium,potassium, calcium and magnesium, etc. These salts can easily beprepared by simply treating the aforementioned spiro-imide compoundswith an aqueous solution of the desired pharmacologically acceptablebase, such as the hydroxide, carbonate or bicarbonate of one of theaforementioned cations, and then evaporating the resulting solution todryness while preferably being placed under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the said acidic compounds and the desired alkali metalalkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents should be employed in order to ensurecompleteness of reaction and maximum yields of the desired finalproduct.

As previously indicated, the spiro-imide compounds of this inventionreduce lens sorbitol levels in diabetic subjects. For instance,2,3-dihydro-spiro-]1H-indene-1,3'-pyrrolidine]-2',5'-dione, a typicaland preferred agent of the present invention, has been found to inhibitthe formation of sorbitol levels in the sciatic nerve of diabetic ratsto a significant degree when given by the oral route of administrationat a dose level as low as 2.5 mg./kg. without showing any substantialsigns of toxic side effects. The other compounds of this invention alsocause similar results. Furthermore, the herein described compounds canbe administered by either the oral or parenteral routes ofadministration without causing any significant untoward pharmacologicalside reactions in the subjects to whom they are so administered. Thesecompounds are ordinarily administered in dosages ranging from about 0.25mg. to about 25 mg. per kg. of body weight per day, although variationswill necessarily occur depending upon the actual condition of thesubject being treated and the particular route of administration chosen.

The spiro-imide compounds of this invention may be administered eitheralone or in combination with pharmaceutically acceptable carriers, andsuch administration can be carried out in both single and multipledosages. The compounds of this invention can be administered in a widevariety of dosage forms, i.e., they may be combined with variouspharmaceutically-acceptable inert carriers in the form of tablets,capsules, lozenges, troches, hard candies, powders, sprays, aqueoussuspensions, injectable solutions, elixirs, syrups, and the like. Suchcarriers include solid diluents or fillers, sterile aqueous media andvarious non-toxic organic solvents. The oral pharmaceutical formulationscan be suitably sweetened and/or flavored by means of various agents ofthe type commonly employed for such purposes. In general, the compoundsof the invention are present in such dosage forms at concentrationlevels ranging from about 0.5% to about 90% by weight of the totalcomposition, i.e., in amounts which are sufficient to provide thedesired unit dosage.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and calciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in soft andhard-filled gelatin capsules; preferred materials in this connectionwould also include the high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the essential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes, and if sodesired, emulsifying and/or suspending agents as well, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

For parenteral administration, solutions of these spiro-imides in sesameor peanut oil or in aqueous propylene glycol or N,N-dimethylformamidemay be employed, as well as sterile aqueous solutions of thecorresponding water-soluble, alkali metal or alkaline-earth metal saltspreviously enumerated. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. These particular aqueous solutionsare especially suitable for intravenous, intramuscular, subcutaneous andintraperitoneal injection purposes. The sterile aqueous media employedare all readily obtainable by standard techniques well-known to thoseskilled in the art. Additionally, it is also possible to administer theaforesaid spiro-imide compounds topically via an appropriate ophthalmicsolution which can then be applied dropwise to the eye.

The activity of the compounds of the present invention, as agents forthe control of chronic diabetic complications, is determined by theirability to successfully pass one or more of the following standardbiological and/or pharmacological tests, viz., (1) measuring theirability to reduce or inhibit sorbitol accumulation in the sciatic nerveof acutely streptozotocinized (i.e., diabetic) rats; (2) measuring theirability to reverse already-elevated sorbitol levels in the sciatic nerveand lens of chronic streptozotocin-induced diabetic rats; (3) measuringtheir ability to prevent or inhibit galactitol formation in the lens ofacutely galactosemic rats, and (4) measuring their ability to delaycataract formation and reduce the severity of lens opacities in chronicgalactosemic rats.

PREPARATION A

6-Fluoro-4-chromanone was prepared according to the procedure describedby R. Sarges in U.S. Pat. No. 4,117,230, starting fromβ-(p-fluorophenoxy)propionic acid [Finger et al., Journal of theAmerican Chemical Society, Vol. 81, p. 94 (1959)] and usingpolyphosphoric acid as the condensing agent. The product obtained wasidentical in every respect with the prior art compound.

PREPARATION B

6,7-Dichlorothiochroman-4-one was prepared according to the proceduredescribed by R. Sarges in U.S. Pat. No. 4,117,230, starting from3,4-dichlorobenzenethiol (available from the Aldrich Chemical Company,Inc., Milwaukee, Wis.) and proceeding thruβ-(3,4-dichlorophenylthio)propionic acid, which was then condensed inthe presence of concentrated sulfuric acid to afford the desiredproduct. The latter material was identical in every respect with theprior art compound.

PREPARATION C

The procedure described by J. A. Faust et al., in the Journal of theAmerican Pharmaceutical Association, Vol. XLVI, No. 2, p. 118 (1957),for the preparation of1,2,3,4-tetrahydro-spiro-[naphthalene-2,3'-pyrrolidine]-2',5'-dione,starting from 2-carboxy-1,2,3,4-tetrahydronaphthaleneacetic acid andusing 28% aqueous ammonia as the reagent, was followed here except that1-carboxy-1,2,3,4-tetrahydro-1-naphthaleneacetic acid was the actualstarting material employed in place of the corresponding 2-positionalisomer. In this particular case, the corresponding final productobtained was3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione, m.p.153°-156° C. (literature m.p. 155°-157° C., according to R. V. Sandbergin U.S. Pat. No. 3,507,881).

Anal. Calcd. for C₁₃ H₁₃ NO₂ : C, 72.54; H, 6.09; N, 6.51. Found: C,72.19; H, 6.17; N, 6.30.

EXAMPLE 1

A mixture consisting of 10 g. (0.0758 mole) of 1-indanone (availablefrom the Aldrich Chemical Company, Inc., Milwaukee, Wis.), 12 ml. (12.6g., 0.1115 mole) of ethyl cyanoacetate, 3 ml. of glacial acetic acid and3 g. of ammonium acetate in 100 ml. of benzene was heated under refluxin a suitable reaction flask equipped with a Dean-Stark trap (waterseparator) for a period of 18 hours. An additional 2 g. of ammoniumacetate were then added, followed by further refluxing for a period of24 hours. At the end of this time, the spent reaction mixture was cooledto room temperature (˜25° C.), diluted with benzene and then washed withwater. The separated organic layer was subsequently dried over anhydrousmagnesium sulfate and filtered, followed by removal of the solvent viaevaporation under reduced pressure. In this manner, there was obtained acrystalline residue which was later recrystallized from ethyl acetate toyield 12 g. (70%) of pure α-cyano-α-(2,3-dihydro-1H-indene-1-ylidene)acetic acid ethyl ester, m.p. 98°-101° C.

To a stirred solution consisting of 3.0 g. (0.0132 mole) of the1-indenylidene compound obtained above dissolved in 20 ml. of ethanol atroom temperature (˜25° C.), there were added 2.5 g. (0.0385 mole) ofpotassium cyanide dissolved in 20 ml. of water. The resulting mixturewas then refluxed for a period of 20 minutes and at the end of thistime, it was cooled and subsequently acidified with concentratedhydrochloric acid. The spent reaction mixture was then extracted threetimes with benzene and the benzene layers were saved, and subsequentlycombined and evaporated to near dryness while under reduced pressure toafford a highly viscous residue. The latter residue was then dissolvedin 15 ml. of glacial acetic acid, and the resulting solutionsubsequently treated with 28 ml. of 12 N hydrochloric acid and refluxedfor a period of 48 hours. At the end of this time, the strongly acidsolution was cooled to room temperature and concentrated in vacuo toafford a residue that later was triturated with water. The precipitatedsolids so obtained were then recovered by means of suction filtrationand thereafter recrystallized from ethanol to give 1.26 g. (43%) of pure(2,3-dihydro-1 H-indene-1-yl)butanedioic acid, m.p. 185°-187° C.

Anal. Calcd. for C₁₂ H₁₂ O₄ : C, 65.44; H, 5.49. Found: C, 65.39; H,5.53.

A mixture consisting of 3.0 g (0.0136 mole) of the above diacid and 3.5ml. of concentrated ammonium hydroxide was heated in an oil bathmaintained at 260° C., allowing the liquid to be removed from themixture by means of distillation under reduced pressure (a pressure of60 mm. Hg was actually employed). The residue so obtained was thentriturated with isopropanol, and the resulting precipitated solids weresubsequently recovered by means of suction filtration and thereafterrecrystallized from ethyl acetate to yield 1.3 g. (48%) of pure2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione, m.p.148°-150° C.

Anal. Calcd. for C₁₂ H₁₁ NO₂ : C, 71.72; H, 5.51; N, 6.96. Found: C,71.31; H, 5.56; N, 6.93.

EXAMPLE 2

A mixture consisting of 3.0 g. (0.017 mole) of 6-chloro-4-chromanone(available from the Aldrich Chemical Company, Inc., Milwaukee,Wisconsin), 15 ml. (15.75 g., 0.1394 mole) of ethyl cyanoacetate and 10g. of ammonium acetate in 300 ml. of benzene was heated according to theprocedure described in Example 1 (where the corresponding 1-indanonecompound was the starting material employed) to give 1.3 g. (29%) ofcrude ethylα-cyano-α-(6-chloro-2,3-dihydro-4H-1-benzopyran-4-ylidene)acetic acidethyl ester, which was used in the next reaction step without anyfurther purification being necessary.

To a stirred solution consisting of the above benzopyranylidene compound(1.3 g., 0.00493 mole) in 9.5 ml. of ethanol, there were added 1.13 g.of potassium cyanide in 9.5 ml. of water and the resulting mixture wasrefluxed according to the procedure described in Example 1 (where thecorresponding 1-indenylidene compound was the starting materialemployed) and worked up in essentially the same manner as before (exceptthat the residue was dissolved in 6 ml. of glacial acetic acid andtreated with 12.7 ml. of concentrated hydrochloric acid prior torefluxing for the last time). In this manner, there was ultimatelyobtained 0.39 g. (29%) of crudeα-(6-chloro-2,3-dihydro-4H-1-benzopyran-4-yl)butanedioic acid, m.p.189°-190.5° C. after further recrystallization from ethanol.

A mixture consisting of 237 mg. (0.00088 mole) of the above diacid and4.5 ml. of concentrated ammonium hydroxide was then heated in the samemanner as described in Example 1 for the corresponding1-carboxy-1-indanacetic acid and isolated in the same manner as beforeto give pure6-chloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione,m.p. 225°-226° C. after recrystallization from ethylacetate/ethanol/n-hexane.

Anal. Calcd. for C₁₂ H₁₀ ClNO₃ : C, 57.27; H, 4.00; N, 5.57. Found: C,57.25; H, 4.00; N, 5.54.

EXAMPLE 3

A mixture consisting of 10 g. (0.0758 mole) of 2-indanone (availablefrom the Aldrich Chemical Company, Inc., Milwaukee, Wis.), 8.6 g.(0.0761 mole) of ethyl cyanoacetate, 1 ml. of piperidine and 1 ml. ofglacial acetic acid in 65 ml. of benzene was heated under reflux insuitable reaction flask equipped with a Dean-Stark trap for a period of18 hours. Upon completion of this step, the reaction mixture was cooledto room temperature (˜25° C.) and poured into 250 ml. of water, followedby separation of the resulting organic layers and then drying of sameover anhydrous magnesium sulfate. After removal of the drying agent bymeans of filtration and the solvent by means of evaporation underreduced pressure, there was obtained a crystalline residue, which wassubsequently recrystallized from n-hexane to yield 6.5 g. (38%) of pureα-cyano-α-(2,3-dihydro-1H-indene-2-ylidene)acetic acid ethyl ester, m.p.112°-114° C. [literature m.p. 116° C., according to the Journal of theChemical Society, Vol. 115, p. 150 (1919)].

Anal. Calcd. for C₁₄ H₁₃ NO₂ : C, 73.99; H, 5.76; N, 6.17. Found: C,74.10; H, 5.84; N, 6.22.

To a stirred solution consisting of 6.5 g. (0.0286 mole) of the2-indenylidene compound obtained above dissolved in 35 ml. of ethanol atroom temperature, there were added 3.8 g. (0.0385 mole) of potassiumcyanide dissolved in 35 ml. of water and the resulting mixture wasrefluxed for a period of 15 minutes according to the procedure describedin Example 1 (where the corresponding 1-indanone compound was thestarting material employed) and worked up in essentially the same manneras before (except that ethyl acetate rather than benzene was the solventemployed in the extraction step, and the residue was dissolved in 25 ml.of glacial acetic acid and treated with 50 ml. of concentratedhydrochloric acid prior to refluxing for the last time). However, inthis particular case, the final residue obtained was diluted with 50 ml.of water and then extracted three times with ethyl acetate, followed bya re-extraction of the combined organic layers (three times) with diluteaqueous sodium bicarbonate solution. On acidification of the combinedaqueous layers with 6 N hydrochloric acid, there was finally obtained afine crystalline precipitate, which was subsequently collected by meansof suction filtration and air dried to constant weight to yield 4.5 g.of crude product. Recrystallization of the latter material from ethylacetate/n-hexane then gave 3.1 g. (49%) of pureα-(2,3-dihydro-1H-indene-2-yl)butanedioic acid, m.p. 166°-168° C.

A mixture consisting of 1.5 g. (0.0068 mole) of the above diacid and 2.0ml. of concentrated ammonium hydroxide was heated gradually to 300° C.(bath temperature) according to the same general procedure described inExample 1 for the preparation of the corresponding 1-isomer. The residueso obtained was then cooled to room temperature and dissolved in 200 ml.of isopropanol, followed by treatment with charcoal and filtration inthe usual manner. The clear alcoholic filtrate which resulted was thenconcentrated in vacuo to ca. 75 ml. and the desired product was allowedto crystallize slowly therefrom while at room temperature. Theprecipitated solids (480 mg.) were subsequently collected by means ofsuction filtration and thereafter recrystallized from isopropanol togive 260 mg. (19%) of pure2,3-dihydro-spiro-[1H-indene-2,3'-pyrrolidine]-2',5'-dione, m.p.173°-175° C.

Anal. Calcd. for C₁₂ H₁₁ NO₂ : C, 71.62; H, 5.51; N, 6.96. Found: C,71.65; H, 5.58; N, 6.91.

EXAMPLE 4

A mixture consisting of 10 g. (0.0657 mole) of6,7-dihydrobenzo(b)thiophene-4(5H)-one (available from the AldrichChemical Company, Inc., Milwaukee, Wis.), 7.5 g. (0.0664 mole) of ethylcyanoacetate, 1 ml. of piperidine and 1 ml. of glacial acetic acid in 65ml. of benzene was heated according to the general procedure describedin Example 1 (where the corresponding 1-indanone compound was thestarting material employed) to ultimately give (after distillation ofthe oily residue) 4.5 g. (28%) of pureα-cyano-α-[6,7-dihydro-5H-benzo(b)thiophene-4-ylidine]acetic acid ethylester, b.p. 156°-160° C./0.3 mm Hg.

To a stirred solution consisting of 4.5 g. (0.0182 mole) of the4-thiopheneylidene compound obtained above dissolved in 20 ml. ofethanol, there were added 2.34 g. (0.036 mole) of potassium cyanidedissolved in 20 ml. of water and the resulting mixture was refluxedaccording to the procedure described in Example 1 (where thecorresponding 1-indenylidene compound was the starting materialemployed) and work-up in essentially the same manner as before. In thismanner, there were ultimately obtained 2.83 g. (65%) of pureα-[6,7-dihydro-5H-benzo(b)thiophene-4-yl]butanedioc acid, m.p. 164°-167°C.

A mixture consisting of 1.4 g. (0.00583 mole) of the above diacid and2.0 ml. of concentrated ammonium hydroxide was then heated in the samemanner as described in Example 1 for the corresponding1-carboxy-1-indanacetic acid and isolated in the same manner as beforeto ultimately yield 290 mg. (23%) of pure6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dione,m.p. 188°-190° C. after recrystallization from isopropanol/diethylether.

Anal. Calcd. for C₁₁ H₁₁ NO₂ S: C, 59.70; H, 5.01; N, 6.33. Found: C,59.87; H, 5.17; N, 6.48.

EXAMPLE 5

A solution consisting of 760 mg. (0.0048 mole) of α-cyanotetralin[Chemical Abstracts, Vol. 47, p. 80576 (1953)] dissolved in 15 ml. ofdry dimethylformamide was heated to 45° C. in a three-neckedround-bottomed reaction flask, while under a dry nitrogen atmosphere,with 228 mg. (0.0050 mole) of 56% sodium hydride (in mineral oil) for aperiod of 45 minutes. At the end of this time, 0.6 ml. (969 mg., 0.00723mole) of 3-bromopropanenitrile was added to the mixture and the lattermixture was then stirred at room temperature (˜25° C.) overnight for aperiod of approximately 16 hours. The resulting reaction mixture wasthen diluted with water, followed by the addition of 600 ml. of ethylacetate to the cooled aqueous mixture. The separated organic layer wasthen washed with water and dried over anhydrous magnesium sulfate. Afterremoval of the drying agent by means of filtration and the solvent bymeans of evaporation under reduced pressure, there was obtained 1.1 g.of crude α-(3,4-dihydro-2H-naphthalene-1-yl)-n-pentane-1,5-dinitrile inthe form of an oil as residue.

A mixture consisting of 2.2 g. (0.0105 mole) of the above crudedinitrile in 25 ml. of ethanol and 23 ml. of 4 N aqueous potassiumhydroxide was heated under reflux for a period of two days. At the endof this time, the reaction mixture was cooled to room temperature (˜25°C.) and diluted with 50 ml. of water and 300 ml. of methylene chloride,followed by treatment with 3 N hydrochloric until acidification wasachieved. The resulting organic layer was then collected andsubsequently extracted three times with 4 N aqueous potassium hydroxidesolution, followed by acidification of the combined aqueous layers andtheir subsequent extraction with fresh methylene chloride. Upon removalof the latter solvent from the final (i.e., separated) organic layer bymeans of evaporation under reduced pressure, there was obtained acrystalline residue which was subsequently recrystallized from ethylenechloride/n-hexane/diethyl ether to give 628 mg. (24%) of pureα-(3,4-dihydro-2H-naphthalene-1-yl)-n-pentane-1,5-dioic acid monoamide,m.p. 143°-145° C.

Anal. Calcd. for C₁₄ H₁₇ NO₃ : C, 67.99; H, 6.93; N, 5.66. Found: C,67.50; H, 6.68; N, 5.47.

A mixture consisting of 600 mg. (0.00243 mole) of the above acid-amideand 20 ml. of concentrated ammonium hydroxide was heated according tothe same general procedure described in Example 1 for a period of threehours to ultimately give (after isolation in the usual manner as before)343 mg. (62%) of pure3,4-dihydro-spiro-[2H-naphthalene-1,3'-piperidine]-2',6'-dione, m.p.173°-175° C. after recrystallization from ethanol/n-hexane.

Anal. Calcd. for C₁₄ H₁₅ NO₂ : C, 73.34; H, 6.59; N, 6.11. Found: C,73.24; H, 6.47; N, 6.09.

EXAMPLE 6

The following spiro-imide compounds may be prepared by employing theprocedures described in the previous examples, starting from readilyavailable materials in each instance:

6-methoxy-2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione.

6-fluoro-2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione.

5,6-dimethoxy-2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione.

5-methoxy-2,3-dihydro-spiro-[1-H-indene-2,3'-pyrrolidine]-2',5'-dione.

6-chloro-2,3-dihydro-spiro-[1H-indene-1,3'-piperidine]-2',5'-dione.

6-bromo-2,3-dihydro-spiro-[1H-indene-2,3'-pyrrolidine]-2',5'-dione.

5-methyl-2,3-dihydro-spiro-[1H-indene-1,3'-piperidine]-2',5'-dione.

6-(n-butyl)-spiro-[1H-indene-2,3'-pyrrolidine]-2',5'-dione.

5-phenyl-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione.

5,6-dichloro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione.

5,6-dimethyl-spiro-[1H-indene-2,3'-pyrrolidine]-2',5'-dione.

7-methoxy-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione.

6,7-dimethoxy-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione.

6-methoxy-3,4-dihydro-spiro-[2H-naphthalene-1,3'-piperidine]-2',5'-dione.

5-methoxy-3,4-dihydro-spiro-[2H-naphthalene-2,3'-pyrrolidine]-2',5'-dione.

7-fluoro-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione.

7-chloro-3,4-dihydro-spiro-[2H-naphthalene-1,3'piperidine]-2',5'-dione.

6-bromo-3,4-dihydro-spiro-[2H-naphthalene-2,3'-pyrrolidine]-2',5'-dione.

6-methyl-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione.

7-(n-butoxy)-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione.

6-phenyl-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione

6,7-dichloro-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione.

6,7-diethyl-3,4-dihydro-spiro-[2H-naphthalene-1,3'-piperidine]-2',5'-dione.

6,7-dimethoxy-3,4-dihydro-spiro-[2H-naphthalene-2,3'-pyrrolidine]-2',5'-dione.

6-methoxy-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione.

6-methoxy-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione.

6-fluoro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione.

6,7-dichloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione.

6,8-dichloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-piperidine]-2',5'-dione.

8-chloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione.

6-bromo-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-piperidine]-2',5-dione.

6,8-dimethyl-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione.

6-(n-butyl)-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione.

7-methyl-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-piperidine]-2',5'-dione.

6-(n-butoxy)-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione.

6,7-dimethoxy-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione.

7-phenyl-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione.

2,3-dihyro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione.

6-methoxy-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione.

6-chloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione.

6-bromo-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-piperidine]-2',5'-dione.

6,7-dichloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione.

6-fluoro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione.

8-chloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione.

7-chloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-piperidine]-2',5'-dione.

6-methyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione.

7-(n-butyl)-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione.

7-(n-butoxy)-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione.

6-phenyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'dione.

6,8-dichloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-piperidine]-2',5'-dione.

6,7-dimethyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione.

6,7-dimethoxy-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione.

2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1-oxide.

6-fluoro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1-oxide.

8-chloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1-oxide.

6-bromo-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-piperidine]-2',5'-dione-1-oxide.

6-methyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1-oxide.

6-methoxy-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1-oxide.

6-phenyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1-oxide.

6,8-dichloro-2,3-dihydro-spiro-[1H-1-benzothiapyran-4,3'-piperidine]-2',5'-dione-1-oxide.

6,7-dimethyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1-oxide.

6,7-dimethoxy-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1-oxide.

2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1,1-dioxide.

6-fluoro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1,1-dioxide.

8-chloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1,1-dioxide.

6-methyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1,1-dioxide.

6-methoxy-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1,1-dioxide.

6-phenyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1,1-dioxide.

6,8-dichloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-piperidine]-2',5'-dione-1,1-dioxide.

6,7-dimethyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1,1-dioxide.

6,7-dimethoxy-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1,1-dioxide.

2-chloro-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2-bromo-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2-methyl-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2-methoxy-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2-phenyl-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2,3-dichloro-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2,3-dimethyl-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2,3-dimethoxy-6,7-dihydro-spiro-[5H-benzo(b)-thiophene-4,3'-pyrrolidine]-2',5'-dione.

spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2-chloro-spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2-(n-propyl)-spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2-ethoxy-spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2-phenyl-spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2,3-dichloro-spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

2,3-dimethyl-spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione.

6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2-chloro-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2-methyl-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2-methoxy-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2-phenyl-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2,3-dichloro-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2,3-dimethyl-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2,3-dimethoxy-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione.

spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2-chloro-spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2-methyl-spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2-methoxy-spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2-phenyl-spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2,3-dichloro-spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione.

2,3-dimethyl-spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione.

EXAMPLE 7

The sodium salt of3,4-dihydro-spiro-[1H-indene-1,3'-pyrrolidino]-2',5'-dione may beprepared by dissolving said compound in water containing an equivalentamount in moles of sodium hydroxide and then freeze-drying the mixture.In this way, the desired alkali metal salt of the imide is obtained inthe form of an amorphous powder which is freely-soluble in water.

In like manner, the potassium and lithium salts are also similarlyprepared, as are the other alkali metal salts of all the otherspiro-imide compounds of this invention which are reported earlier inPreparation C and Examples 2-6, respectively.

EXAMPLE 8

The calcium salt of2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione may beprepared by dissolving said compound in water containing an equivalentamount in moles of calcium hydroxide and then freeze-drying the mixture.The corresponding magnesium salt is also prepared in like manner, as areall the other alkaline-earth metal salts not only of this particularcompound, but also of those spiro-imides previously described inPreparation C and Examples 2-6, respectively.

EXAMPLE 9

A dry solid pharmaceutical composition may be prepared by blending thefollowing materials together in the proportions by weight specifiedbelow:

    ______________________________________                                        3,4-dihydro-spiro-                                                            [H-indene-1,3'-pyrrolidine]-                                                  2',5'-dione               50                                                  Sodium citrate            25                                                  Alginic acid              10                                                  Polyvinylpyrrolidone      10                                                  Magnesium stearate         5                                                  ______________________________________                                    

After the dried compound is thoroughly blended, tablets are punched fromthe resulting mixture, each tablet being of such size that it contains200 mg. of the active ingredient. Other tablets are also prepared in asimilar fashion containing 25, 50 and 100 mg. of the active ingredient,respectively, by merely using the appropriate amount of the spiro-imidecompound in each case.

EXAMPLE 10

A dry solid pharmaceutical composition may be prepared by combining thefollowing materials together in the proportions by weight indicatedbelow:

    ______________________________________                                        2,3-Dihydro-[1H-indene-1,3-pyrrolidine]-                                      2',5'-dione               50                                                  Calcium carbonate         20                                                  Polyethylene glycol, average molecular                                        weight 4000               30                                                  ______________________________________                                    

The dried solid mixture so prepared is then thoroughly agitated so as toobtain a powdered product that is completely uniform in every respect.Soft elastic and hard-filled gelatin capsules containing thispharmaceutical composition are then prepared, employing a sufficientquantity of material in each instance so as to provide each capsule with250 mg. of the active ingredient.

EXAMPLE 11

The following spiro-imide compounds of Preparation C and Examples 1-5,respectively, were tested for their ability to reduce or inhibitsorbitol accumulation in the sciatic nerve of streptozotocinized (i.e.,diabetic) rats essentially by the procedure described in U.S. Pat. No.3,821,383. In the present study, the amount of sorbitol accumulation inthe sciatic nerves was measured 27 hours after induction of diabetes.The compounds were administered orally at the dose levels indicated 4, 8and 24 hours following the administration of streptozotocin. The resultsobtained in this manner are presented below in terms of percentinhibition (%) afforded by the test compound as compared to the casewhere no compound was administered (i.e., the untreated animal wheresorbitol levels normally rise from approximately 50-100 mM/g. tissue toas high as 400 mM/g. tissue in the 27-hour test period):

    ______________________________________                                                    Percent Inhibition (%)                                            Compound      2.5      5.0       25 mg./kg.                                   ______________________________________                                        Product of Prep. C                                                                          --       46        --                                           Product of Ex. 1                                                                            28       --        --                                           Product of Ex. 2                                                                            --       13        --                                           Product of Ex. 3                                                                            --       --        33                                           Product of Ex. 4                                                                            --       --        51                                           Product of Ex. 5                                                                            --       --        23                                           ______________________________________                                    

What is claimed is:
 1. A method for lowering sorbitol levels in thesciatic nerve of a diabetic host, which comprises administering to saidhost an effective amount of a compound selected from the groupconsisting of spiro-imides of the formulae: ##STR6## and the base saltsthereof with pharmacologically acceptable cations, whereinW is--(CH₂)_(n) --; X is hydrogen, chlorine, lower alkyl or lower alkoxyeach having up to four carbon atoms; X¹ is hydrogen, fluorine, chlorine,bromine, lower alkyl having up to four carbon atoms, lower alkoxy havingup to four carbon atoms or phenyl, with the proviso that when X¹ isfluorine, bromine or phenyl, X is hydrogen; Y is oxygen or sulfur; Z isW, Y or Q wherein Q is oxosulfur or dioxosulfur; m is one; and n is zeroor one.
 2. The method as claimed in claim 1 wherein the compoundadministered is2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione.
 3. Themethod as claimed in claim 1 wherein the compound administered is2,3-dihydro-spiro-[1H-indene-2,3'-pyrrolidine]-2',5'-dione.
 4. Themethod as claimed in claim 1 wherein the compound administered is3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione.
 5. Themethod as claimed in claim 1 wherein the compound administered is6-chloro-2,3-dihydro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione. 6.The method as claimed in claim 1 wherein the compound administered is6,7-dihydro-spiro-[5H-benzo(b)-thiophene-4,3'-pyrrolidine]-2',5-dione.7. A composition suitable for oral administration comprising apharmaceutically acceptable carrier and a compound of Formula I or II ofclaim 1 wherein Z is other than W in an amount effective for thetreatment of diabetes-associated chronic complications.